Specific antibody deficiency

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Specific antibody deficiency

Presented by Jaichat Mekaroonkamol, MD.

Jan17, 2014

Published in: Health & Medicine, Technology

Specific antibody deficiency

  1. 1. SPECIFIC ANTIBODY DEFICIENCY (SAD) Jaichat Mekaroonkamol, MD.
  2. 2. OUTLINES  Definition and Terminology  Indication for evaluation  Epidermiology  Clinical syndromes  Pathogenesis  Evaluation and diagnosis  Treatment  Prognosis
  3. 3. DEFINITION “Specific antibody deficiency with normal serum immunoglobulin only deficient specific antibody response to polysaccharide antigens” Notarangelo L. et al. JACI 010
  4. 4. TERMINOLOGY  Specific antibody deficiency  Selective antibody deficiency with normal immunoglobulin  Impaired polysaccharide responsiveness  Polysaccharide nonresponse
  5. 5. INDICATIONS FOR EVALUATION  Recurrent or severe sinopulmonary infections  Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis or Staphylococcus aureus  Otitis media, Bronchitis, acute and chronic rhinosinusitis, pneumonia, bronchiectasis
  6. 6. Pediatr Allergy Immunol 2008: 19: 505–512
  7. 7. Pediatr Allergy Immunol 2008: 19: 505–512
  8. 8. RECURRENT INFECTIONS Middleton’s Allergy, 8th ed
  9. 9. School age 4 Infancy 11 Pre-school 8 Pediatr Allergy Immunol 2008: 19: 505–512
  10. 10. 10 WARNING SIGNS 10
  11. 11. 10 WARNING SIGNS: ADULT (>18 YEAR OLD) 11
  12. 12. Suspect Immunodeficiency
  13. 13. RECURRENT INFECTIONS Middleton’s Allergy, 8th ed
  14. 14. RECURRENT INFECTIONS Middleton’s Allergy, 8th ed
  15. 15. RECURRENT INFECTIONS Middleton’s Allergy, 8th ed
  16. 16. NATURE REVIEWS | IMMUNOLOGY , 2013
  17. 17. 52.2% 25.4% 10.4% 12% J Clin Immunol, 2009
  18. 18. 30% Prevalence 7-19% J Clin Immunol, 2009
  19. 19.  Royal Children’s Hospital, Melbourne between 1 January 2004 and 30 June 2005  Age 2–18 years at the time of evaluation  Suspected antibody deficiency: 10 warning signs : 74 patients  An adequate IgG antibody response   post-immunization antibody >/= 1·3 µg/ml fourfold increase over the preimmunization value  SAD : response to less than 50% of the serotypes tested (11 patients: 14.9%) BolyeRJ. et al. ClinExp Immunol. 2006 Dec;146(3):486-92
  20. 20. Exclusion criteria • An identified primary or secondary immune disorder including isolated IgG, IgG2 or IgA deficiency • Immunosuppressive medication • Anatomical abnormalities
  21. 21. BolyeRJ. et al. ClinExp Immunol. 2006 Dec;146(3):486-92
  22. 22. RR of chronic otorrhoea in those with allergic rhinitis 0·85 (P = 0·28) Independent BolyeRJ. et al. ClinExp Immunol. 2006 Dec;146(3):486-92
  23. 23. NATURE REVIEWS | IMMUNOLOGY , 2013
  24. 24. HUMORAL IMMUNE RESPONSE T dependent responses  T independent responses Abbas. Cellular and Molecular immunology. Seventh Edition
  25. 25. T Dependent & Independent Antigens T Dependent Antigens Induces response in babies Induces response in athymia Primes T cells Polyclonally activates B cells Requires repeating epitopes TI-1 Antigens TI-2 Antigens Yes No Yes No No Yes Yes No Yes No No Yes No No Yes TD: Activate B-1 and B-2 B cells TI-1: Activate B-1 and B-2 B cells TI-2: Activate only B-1 B cells Examples TD: Diptheria toxin, influenza heamagglutinin, Mycobacterium tuberculosis TI-1: Bacterial lipopolysaccharides, Brucella abortis TI-2: Pneumococcal polysaccharides, Salmonella polymerised flagellin
  26. 26. B LYMPHOCYTE SUBSETS Abbas. Cellular and Molecular immunology. Seventh Edition
  27. 27. Abbas. Cellular and Molecular immunology. Seventh Edition
  28. 28. BACTERIAL POLYSACCHARIDES
  29. 29. NATURE REVIEWS | IMMUNOLOGY , 2013
  30. 30. J. Clin. Invest. 120:214–222 (2010)
  31. 31. IMMUNOLOGY OF BACTERIAL POLYSACCHARIDE ANTIGENS  Innate  immunity Complement activation Alternative: covalent attachment of C3b  Lectin: MBL bind to mannose residues  Common pathway   Activation of phagocytes and inflammation   Phagocytes use surface receptors to recognize: C-type lectin like, scarvenger receptor Toll-like receptors  Adaptive immunity
  32. 32. PATHOGENESIS  Not fully understood  Different defects may result in the same problem  Delayed maturation of the immune system Rijkers GT immunodeficiency. 1993;5(1):1-21.
  33. 33. Middleton’s Allergy, 8th ed
  34. 34. EVALUATIONS  Immunoglobuline levels: IgG, IgA and IgM  IgG subclass levels  Response to protein vaccines “Only identifiable abnormality is the response to polysaccharide vaccines” Rijkers GT immunodeficiency. 1993;5(1):1-21.
  35. 35. PNEUMOCOCCAL VACCINATION  Number of serotypes used varies from 4 to 23, 12 to 14 are most commonly used  At least 4 weeks after vaccination  Same laboratory perform
  36. 36. Children with recurrent respiratory infections between 1995 and 1997  Without immunoglobulin, IgG subclass, or other known primary or secondary Immunodeficiency  A total of 113 patients  J ALLERGY CLIN IMMUNOL, AUGUST 1998
  37. 37. Adequate IgG antibody response • Post titer >/= 1.3 µg/ml • Minimum fourfold increase over the baseline J ALLERGY CLIN IMMUNOL, AUGUST 1998
  38. 38. J ALLERGY CLIN IMMUNOL, AUGUST 1998
  39. 39. J ALLERGY CLIN IMMUNOL, AUGUST 1998
  40. 40. J ALLERGY CLIN IMMUNOL, AUGUST 1998
  41. 41. J ALLERGY CLIN IMMUNOL, AUGUST 1998
  42. 42. Pneumococcal IgG antibody responses  Normal  24 mo – 5 yr   response “protective’’ antibodies to 50% or more of the serotypes tested, with at least a 2-fold increase in the titers 6-65 yr  “protective’’ antibodies to 70% or more of the serotypes tested, with at least a 2-fold increase in the titers  Protective  level ≥ 1.3 mcg/ml J Allergy Clin Immunol 2012
  43. 43. PROTECTIVE TITER  “antibody titers ≥ 200 ng of AbN/ml : decreased nasopharyngeal colonization with specific pneumococcal serotypes” in children  the conversion factor is 160 ng of antibody N/ml to 1 microgram/mL.
  44. 44. DECREASED NASOPHARYNGEAL COLONIZATION Lancet Infect Dis 2004; 4: 144–54
  45. 45. A cohort study  95 immunocompetent children and 22 HIV-infected children  Ages 2 to 15 years  PPV J Allergy Clin Immunol, 2006;118:1336-41
  46. 46. Pre-PPV titer, microgram/ml +/- SD HIV: 1.5 +/- 1.2 Control: 1.3 +/- 0.7   J Allergy Clin Immunol, 2006;118:1336-41
  47. 47. J Allergy Clin Immunol, 2006;118:1336-41
  48. 48. “Although no definitive data are available, the recommendation of an expert panel is that an adequate response to 50% or 70% of serotypes tested is a normal response for children or adults, respectively” Bonilla FA. et al. Ann Allergy Asthma Immunol. 2005 J Allergy Clin Immunol, 2006;118:1336-41 J Allergy Clin Immunol. 2009 January ; 123(1): 195–200
  49. 49. J Allergy Clin Immunol 2012
  50. 50. Retrospective chart analysis between 2001 and 2007  Patients had to have received the unconjugated 23valent pneumococcal vaccine  There were 40 children (≤16 years old) and 539 adults  Ages ranged from 4 to 87 years  J Allergy Clin Immunol. 2009 January ; 123(1): 195–200
  51. 51. J Allergy Clin Immunol. 2009 January ; 123(1): 195–200
  52. 52. 10-40 % J Allergy Clin Immunol. 2009 January ; 123(1): 195–200
  53. 53. J Allergy Clin Immunol. 2009 January ; 123(1): 195–200
  54. 54. Pneumococcal IgG antibody responses  Normal  24 mo – 5 yr   response “protective’’ antibodies to 50% or more of the serotypes tested, with at least a 2-fold increase in the titers 6-65 yr  “protective’’ antibodies to 70% or more of the serotypes tested, with at least a 2-fold increase in the titers  Protective  level ≥ 1.3 mcg/ml J Allergy Clin Immunol 2012
  55. 55. Pneumococcal IgG antibody responses J Allergy Clin Immunol 2012
  56. 56. TREATMENT 1. 2. 3. 4. 5. Immunization with conjugate vaccines Aggressive management of conditions predisposing to recurrent sinopulmonary infections Increased vigilance and appropriate antibiotic therapy for infections Prophylactic antibiotics Immunoglobulin replacement
  57. 57. IMMUNIZATION WITH CONJUGATE VACCINES  13-valent pneumococcal conjugate vaccine should be used  80 to 90 percent respond to one dose of the conjugate vaccine  patients who respond to the conjugate vaccine also improve clinically Sorensen RU et al. PediatrInfect DisJ. 1998 Aug;17(8):685-91
  58. 58. Referred for evaluation of recurrent respiratory infections  All enrolled patients were immunized with the experimental 7-valent PCV within 6 months of their immunization with PPV  3 groups  I: PCVPPVPCV 17: 2-13 yr(5.3)  II: PCVPPV(≥3/9 serotypes)PPV 11: 2-8 yr (4.6)  III: PCVPPV single dose 67: 2-13 Yr (5.6)  Sorensen RU et al. PediatrInfect DisJ. 1998 Aug;17(8):685-91
  59. 59. Sorensen RU et al. PediatrInfect DisJ. 1998 Aug;17(8):685-91
  60. 60. Sorensen RU et al. PediatrInfect DisJ. 1998 Aug;17(8):685-91
  61. 61. MMWR / June 28, 2013 / Vol. 62 / No. 25
  62. 62. MMWR / June 28, 2013 / Vol. 62 / No. 25
  63. 63. M. Ballow / Ann Allergy Asthma Immunol 111 (2013)
  64. 64. MMWR / October 12, 2012 / Vol. 61 / No. 40
  65. 65. MMWR / October 12, 2012 / Vol. 61 / No. 40
  66. 66. Clinical Infectious Diseases 2009; 48:S65–74
  67. 67. Clinical Infectious Diseases 2009; 48:S65–74
  68. 68. TREATMENT 1. 2. 3. 4. 5. Immunization with conjugate vaccines Aggressive management of conditions predisposing to recurrent sinopulmonary infections Increased vigilance and appropriate antibiotic therapy for infections Prophylactic antibiotics Immunoglobulin replacement
  69. 69. MANAGEMENT OF SINOPULMONARY DISEASE  Aggressive management of other conditions predisposing to recurrent sinopulmonary infections  Allergic  Prompt rhinitis and asthma recognition and treatment of sinopulmonary bacterial infections
  70. 70. TREATMENT 1. 2. 3. 4. 5. Immunization with conjugate vaccines Aggressive management of conditions predisposing to recurrent sinopulmonaryinfections Increased vigilance and appropriate antibiotic therapy for infections Prophylactic antibiotics Immunoglobulin replacement
  71. 71. ANTIBIOTIC PROPHYLAXIS  Frequency and severity of infections remain high after immunization with conjugate vaccine and management of atopic disease   One of the largest studies examined 120 children aged 2 to 15 years of age 72 % were successfully managed with prophylactic antibiotics WolpertJ. PediatrAsthma Allergy Immunol. 1998; 12:183
  72. 72. ANTIBIOTIC PROPHYLAXIS  No published controlled studies  Regimens were initially derived from a series of immunocompetent patients with recurrent otitis media    Amoxicillin(20 mg/kg per day as a single dose or divided BID) Trimethoprim-sulfamethoxazole(5 mg/kg per day as trimethoprimas a single dose) Azithromycin(10 mg/kg per week) Liston TE et al. Pediatrics 1983; 71:524. Principi N, et al. Am J Dis Child 1989; 143:1414. De Diego JI et al. Int J Pediatr Otorhinolaryngol 2001; 58:47.
  73. 73. Prophylactic antibiotics are not necessary  Prolonged courses (eg, one to three months for chronic sinusitis) to clear infections completely  Administer antibiotics only when there are clinical or laboratory signs of active infection, and to assure that the infection is fully resolved before discontinuation 
  74. 74. TREATMENT 1. 2. 3. 4. 5. Immunization with conjugate vaccines Aggressive management of conditions predisposing to recurrent sinopulmonaryinfections Increased vigilance and appropriate antibiotic therapy for infections Prophylactic antibiotics Immunoglobulin replacement
  75. 75. IMMUNOGLOBULIN REPLACEMENT THERAPY  Recurrent infections that persist after immunizing with conjugate vaccines and appropriate antibiotic  Uncontrollable recurrent otitis media, bronchiectasis  Multiple antibiotic hypersensitivities Zora JA. Ann Allergy. 1993;70(4):283 OrtigasAP. Ann Allergy Asthma Immunol. 1999; 82:71
  76. 76.  Patients with well-documented severe or moderate polysaccharide nonresponsiveness and evidence of recurrent infections, with a proven requirement of antibiotic therapy for improvement
  77. 77. Clinical and Experimental Immunology, 169: 57–69
  78. 78. IMMUNOGLOBULIN REPLACEMENT THERAPY  Retrospective uncontrolled series of pediatric patients ; significant decreases in infections  Based on clinical response, serum trough levels of IgG are NOT helpful  Responses to polysaccharide sometimes improve after treatment for 6 to 24 months and have to be reevaluated Zora JA. Ann Allergy. 1993;70(4):283 OrtigasAP. Ann Allergy Asthma Immunol. 1999; 82:71
  79. 79. Patients received 7 consecutive IVIG infusions 6 serotypes, peak values reached a level > 1.3 mg/mL in 87% to 100% of the patients. Pediatrics 2014;133:e154–e162
  80. 80. Pediatrics 2014;133:e154–e162
  81. 81. PROGNOSIS  Usually benign if they are identified and properly managed  Repeat immune studies after a mean interval of 3.1 years showed 50% of patients developed normal responses  Normalize antibody responses to bacterial polysaccharides by age 5 to 6 years WolpertJ. PediatrAsthma Allergy Immunol. 1998; 12:183
  82. 82.  99 children, mean age 5·9 (range 2–16) years, with recurrent or severe infections Acute otitis media ≥ 5  Sinusitis ≥ 3  Pneumonia ≥ 2  History of severe invasive infection  89 healthy children matched for age and gender  No children had received previous PCV or PPV  Adequate response  respond to 50% or more of the serotypes, with at least a fourfold increase in titre and protective levels ≥ 1·3 mg/ml  Post titer at 2 week of vaccination  Clinical and Experimental Immunology, 2012
  83. 83.  Ten of 91 (11%) children had SAD.  Three children (3%) in control group responded inadequately to PPV 5 responded adequately 8 PPV 3 responded inadequately 10 SAD 2 PCV 0.5-5 years 1 responded adequately Clinical and Experimental Immunology, 2012
  84. 84.  Ten of 91 (11%) children had SAD.  Three children (3%) in control group responded inadequately to PPV Interval?? 3 PPV 4 inadequate PPV PCV 10 months 1 PCV Hypo responsiveness IVIG Clinical and Experimental Immunology, 2012
  85. 85.  Ten of 91 (11%) children had SAD.  Three children (3%) in control group responded inadequately to PPV 3.6 years 1 PPV Responded adequately 2 None recurrent infection 3 Healthy Inadequate 6 years Clinical and Experimental Immunology, 2012
  86. 86. SAD is often transient and resolves itself within a few years without specific treatment Clinical and Experimental Immunology, 2012
  87. 87. CONCLUSIONS SAD = inability to respond to polysaccharide antigens in children over the age of two years  Recurrent sinopulmonary infections with polysacccharide organism: Chronic otorhea  23vPPV is most valuable nonprotein, polysaccharide vaccine for the evaluation of a T-cell independent response  Adequate response depend on age and immunogenic potential of various serotypes  often transient and resolves itself within a few years without specific treatment 
  88. 88. Thank You! L/O/G/O

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